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Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
Although a full understanding of
insulin/insulin-like growth factor (IGF) action is evolving, the
discovery of insulin receptor substrate (IRS) proteins and their role
to link cell surface receptors to the intracellular signaling cascades
provided an important step forward. Moreover, Insulin/IGF receptors use
common signaling pathways to accomplish many tasks, the IRS proteins
add a unique layer of specificity and control. Importantly, the IRS-2
branch of the insulin/IGF-signaling pathway is a common element in
peripheral insulin response and pancreatic 
-cell growth and
function. Failure of IRS-2 signaling might explain the eventual loss of
compensatory hyperinsulinemia during prolonged periods of peripheral
insulin resistance. Moreover, short-term inhibition of IRS protein
functions by serine phosphorylation, or sustained inhibition by
ubiquitin-targeted proteosome-mediated degradation suggests a common
molecular mechanism for insulin resistance during acute injury or
infection, or the sensitivity of -cells to autoimmune destruction.
The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a
common regulatory pathway linking development, somatic growth,
fertility, neuronal proliferation, and aging to the core mechanisms
used by vertebrates for nutrient sensing.
insulin receptor substrate
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